U.S. patent number 4,711,902 [Application Number 06/662,469] was granted by the patent office on 1987-12-08 for medicament formulation.
This patent grant is currently assigned to Bayer Aktiengesellschaft. Invention is credited to Peter Serno.
United States Patent |
4,711,902 |
Serno |
December 8, 1987 |
**Please see images for:
( Certificate of Correction ) ** |
Medicament formulation
Abstract
A medicament formulation of intravenous injection comprising a
medicinally active compound, a lipid phase, an emulsifier and
water, the lipid phase being present in up to about 30% by weight,
the emulsifier being present in about 0.1 to 10% by weight, and
water being present up to 100%, the lipid phase containing up to
about 50% by weight of a sparingly soluble medicinally active
compound, and consisting essentially of (a) at least one ester
principally of at least one medium chain-length fatty acid, or (b)
a mixture of at least one ester principally of at least one medium
chain-length fatty acid with at least one vegetable or animal oil,
the mixture containing at least 10% by weight of the ester
principally of the medium chain-length fatty acid, or (c) at least
one ester principally of at least one medium chain-length fatty
acid, at least one vegetable or animal oil, or a mixture thereof,
in combination with 0.3 to 200% by weight of benzyl alcohol based
on the content of lipid or oil. A greater amount of medicinal agent
can be administered in a reduced total volume of injectable
liquid.
Inventors: |
Serno; Peter (Cologne,
DE) |
Assignee: |
Bayer Aktiengesellschaft
(Leverkusen, DE)
|
Family
ID: |
6213011 |
Appl.
No.: |
06/662,469 |
Filed: |
October 18, 1984 |
Foreign Application Priority Data
|
|
|
|
|
Oct 28, 1983 [DE] |
|
|
3339236 |
|
Current U.S.
Class: |
514/356; 514/359;
514/538; 514/404; 514/937 |
Current CPC
Class: |
A61K
47/14 (20130101); A61K 9/0019 (20130101); A61K
9/1075 (20130101); A61K 31/415 (20130101); A61K
31/44 (20130101); A61K 47/44 (20130101); Y10S
514/937 (20130101) |
Current International
Class: |
A61K
9/107 (20060101); A61K 47/14 (20060101); A61K
47/44 (20060101); A61K 31/415 (20060101); A61K
31/44 (20060101); A61K 031/44 (); A61K 031/41 ();
A61K 031/415 (); A61K 031/24 () |
Field of
Search: |
;514/356,359,538,404 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
3764683 |
October 1973 |
Bosserf et al. |
4237137 |
December 1980 |
Tacke et al. |
4264611 |
April 1981 |
Berntsson et al. |
|
Foreign Patent Documents
Primary Examiner: Brown; J. R.
Assistant Examiner: Rollins, Jr.; John W.
Attorney, Agent or Firm: Sprung Horn Kramer & Woods
Claims
What is claimed is:
1. A medicament formulation in the form of a lipid emulsion for
intravenous injection comprising a medicinally active compound, a
lipid phase, a physiologically tolerated emulsifier and water, the
lipid phase being present in an amount of 5 to 20% by weight, the
emulsifier being present in about 0.1 to 10% by weight, and water
being present up to 100%, the lipid phase containing up to about
50% by weight of a sparingly soluble medicinally active compound,
and an ester component said ester component being
at least one ester of at least one C.sub.6 to C.sub.12 fatty
acid.
2. A formulation according to claim 1, wherein the proportion of
the ester of a medium chain-length fatty acid is at least about 30%
by weight of the lipid phase.
3. A formulation according to claim 1, wherein the ester of a
medium chain-length fatty acid is selected from the group
consisting of a monoester of a monohydric saturated alphatic
C.sub.1 -C.sub.18 alcohol, a monoester of a polyhydric saturated
aliphatic C.sub.1 -C.sub.18 alcohol, a diester of a monohydric
saturated aliphatic C.sub.1 -C.sub.18 alcohol, a diester of a
polyhydric saturated aliphatic C.sub.1 -C.sub.18 alcohol, a
polyester of a monohydric saturated aliphatic C.sub.1 -C.sub.18
alcohol, and a polyester of a polyhydric saturated aliphatic
C.sub.1 -C.sub.18 alcohol with 55 to 100% by weight of at least one
monobasic or dibasic, saturated or unsaturated C.sub.6 -C.sub.12
fatty acid and 0 to 45% by weight of at least one monobasic,
dibasic or polybasic, saturated or unsaturated C.sub.1 -C.sub.5 or
C.sub.13 -C.sub.22 carboxylic acid.
4. A formulation according to claim 3, wherein the alcohol
component of the ester of a medium chain-length fatty acid is a
monohydric to trihydric, aliphatic C.sub.2 -C.sub.6 alcohol.
5. A formulation according to claim 3, wherein the C.sub.6
-C.sub.12 fatty acid is selected from the group consisting of
hexanoic acid, hexenoic acid, hexadienoic acid, octanoic acid,
octenoic acid, octadienoic acid, octatrienoic acid, decanoic acid,
decenoic acid, decadienoic acid, decatrienoic acid, decatetraenoic
acid, dodecanoic acid, dodecadienoic acid, dodecatrienoic acid,
dodecatetraenoic acid and dodecapentaenoic acid.
6. A formulation according to claim 3, wherein the carboxylic acid
is selected from the group consisting of formic acid, acetic acid,
propionic acid, butyric acid, valeric acid, myristic acid, palmitic
acid, stearic acid, arachidic acid, behenic acid, butenoic acid,
hexadecenoic acid, oleic acid, docosenoic acid, linoleic acid,
linolenic acid, arachidonic acid, malonic acid, succinic acid,
glutaric acid, suberic acid, butenedioic acid, glycolic acid,
lactic acid, ricinoleic acid, malic acid, tartaric acid and citric
acid.
7. A formulation according to claim 4, wherein the alcohol
component is selected from the group consisting of glycerol,
propylene 1,2-glycol and mixtures thereof.
8. A formulation according to claim 1, wherein the medicinally
active compound is selected from the group consisting of
dihydropyridines, pharmaceutically active triazoles, muzolimine and
propanidide.
9. A formulation according to claim 1, wherein the medicinally
active compound is a dihydropyridine of the formula ##STR5## in
which R.sub.1 is C.sub.1 -C.sub.4 -alkyl unsubstituted or
substituted by C.sub.1 -C.sub.3 -alkoxy,
R.sub.2 is C.sub.1 -C.sub.10 -alkyl unsubstituted or substituted by
C.sub.1 -C.sub.3 -alkoxy, trifluoromethyl or
N-methyl-N-benzylamino,
R.sub.3 is C.sub.1 -C.sub.4 -alkyl, cyano or hydroxymethyl, and
X is 2- or 3-nitro, 2,3-dichloro or 2,3- .dbd.N--O--N.dbd.
completing a ring.
10. A formulation according to claim 1, wherein the medicinally
active compound is nimodipine.
11. A formulation according to claim 1, wherein said emulsifier is
selected from the group consisting of phospholipids,
polyoxyethylene/polyoxypropylene copolymers, polyethylene glycol
sorbitan fatty acid esters, polyethylene glycol fatty acid esters,
cholesterol, cholesterol esters and sodium salts of fatty
acids.
12. A formulation according to claim 1, wherein the active compound
is a dihydropyridine selected from the group consisting of
nifedipine, nimodipine, nitrendipine, nisoldipine, niludipine,
nicardipin and felodipin.
13. A medicament formulation according to claim 1, wherein the
medium-chain length fatty acid is a C.sub.8 to C.sub.10 fatty
acid.
14. A medicament formulation according to claim 1, wherein said
ester component further comprises 0.3 to 200% by weight of a benzyl
alcohol, based on the content of the fatty acid ester.
15. A medicament formulation according to claim 1, wherein said
ester component further comprises at least one oil selected from
the group consisting of a vegetable oil and an animal oil, the
resultant mixture of the ester and the oil containing at least 10%
by weight of the ester.
16. A formulation according to claim 15, wherein the vegetable or
animal oil comprises soy bean oil, safflower oil, cottonseed oil
and mixtures thereof.
17. A medicament formulation according to claim 1, wherein said
ester component further comprises at least one oil selected from
the group consisting of a vegetable oil and an animal oil and 0.3
to 200% by weight of benzyl alcohol, based on the content of the
lipid phase.
18. A medicament formulation in the form of a lipid emulsion for
intravenous injection comprising a medicinally active
dihydropyridine of the formula ##STR6## in which R.sub.1 is C.sub.1
-C.sub.4 -alkyl unsubstituted or substituted by C.sub.1 -C.sub.3
-alkoxy,
R.sup.2 is C.sub.1 -C.sub.10 -alkyl unsubstituted or substituted by
C.sub.1 -C.sub.3 -alkoxy, trifluoromethyl or
N-methyl-N-benzylamino,
R.sub.3 is C.sub.1 -C.sub.4 -alkyl, cyano or hydroxymethyl, and
X is 2- or 3-nitro, 2,3-dichloro or 2,3- .dbd.N--O--N.dbd.
completing a ring, and a lipid phase, said lipid phase being
(a) at least one ester of a monobasic, saturated C.sub.6 -C.sub.12
fatty acid and a saturated aliphatic C.sub.1 -C.sub.18 alcohol,
or
(b) a mixture of at least one ester according to (a) and at least
one oil selected from the group consisting of a vegetable oil, an
animal oil and a mixture thereof.
19. A medicament formulation according to claim 18, wherein the
saturated aliphatic C.sub.1 -C.sub.18 -alcohol is glycerol.
20. A medicament formulation according to claim 18, wherein the
animal oil is soy bean oil.
21. A process for the preparation of a medicament formulation
according to claim 1, comprising mixing at a temperature of up to
about 75.degree. C. the lipophilic constituents comprising the
esters principally of medium chain-length fatty acids and the
vegetable or animal oils if present, the medicinally active
compound and the benzyl alcohol if present, then vigorously mixing
the mixture with water, thereby to form a pre-emulsion, the
emulsifier being introduced into either or both of the lipophilic
phase or the aqueous phase, and then homogenizing the pre-emulsion
until an emulsion having a mean lipid droplet diameter less than
about 1 .mu.m is produced.
22. A process according to claim 21, wherein the homogenization is
carried out by a high-pressure homogenizer under a pressure up to
about 1,000 bar, or by ultrasonic equipment.
23. A process according to claim 21, wherein the water contains an
agent for producing isotonicity.
24. A process according to claim 21, wherein the homogenization is
carried out by ultrasonic equipment.
Description
The invention relates to a medicament formulation for intravenous
injection, and to a process for its preparation.
It is known that medicinal active compounds can be administered
intravenously only in the dissolved form. Active compounds which
dissolve in water only slightly or not at all have to be induced to
dissolve by solubilizing means.
The means hitherto disclosed, such as the addition of organic
solvents, have proved to be unsatisfactory since, as a consequence
of these additions, unfavorable physiological side effects, such as
injection pain, thrombophlebitis, histaminoid reactions,
bronchospasms or cardiovascular collapse, may occur.
According to DE-AS (German Published Specification) No. 1,792,410,
these disadvantages can be avoided by administering the sparingly
soluble medicaments in the form of a lipid emulsion, consisting of
a vegetable or animal oil, in particular soy bean oil, which is
dispersed in water with the addition of emulsifiers and of agents
to produce isotonicity.
However, this process presupposes that the sparingly soluble
medicaments dissolve in sufficient amounts in vegetable or animal
oils, in particular soy bean oil, but in most cases this is not
guaranteed.
The low solvent power for medicinal active compounds which are
sparingly soluble in water leads to the use of additions of large
amounts which are undesired per se. Due to the addition of these
large amounts, a large amount of liquid is, for a set amount of
active compound, unavoidably introduced into the body. Due to the
high lipid content associated with the administration, there is
likewise introduction of high caloric energy which is
undesired.
It has now been found that a considerable increase in the
solubility in lipid emulsions of medicinal active compounds which
are sparingly soluble in water can be achieved by the following
means:
(1) Use of esters principally of medium chain-length fatty acids as
components in the lipid phase in the emulsion, or
(2) addition of benzyl alcohol to the lipid emulsion, or
(3) combined use of esters principally of medium chain-length fatty
acids and of benzyl alcohol.
Thus the invention relates to a medicament formulation for
intravenous injection containing medicinal active compound, lipid
phase, emulsifier and water, the lipid phase being present in
amounts up to 30% by weight, preferably 5 to 20% by weight, the
emulsifier being present in amounts of 0.1 to 10% by weight, and
water being present up to 100%, and the lipid phase containing up
to 50% by weight of a sparingly soluble medicinal active compound,
and consisting of
(a) esters principally of medium chain-length fatty acids, or
(b) mixtures of esters principally of medium chain-length fatty
acids with vegetable or animal oils containing at least 10% by
weight, preferably at least 30% by weight, of esters principally of
medium chain-length fatty acids, or
(c) esters principally of medium chain-length fatty acids,
vegetable or animal oils, or their mixtures in combination with 0.3
to 200% by weight of benzyl alcohol based on the content of lipid
or oil.
In addition to water for injections, the aqueous phase can contain
up to 10% by weight of customary agents for producing isotonicity,
such as glycerol or xylitol.
Suitable emulsifiers are the physiologically tolerated emulsifiers,
such as phospholipids, polyoxyethylene/polyoxypropylene copolymers,
polyethylene glycol sorbitan fatty acid esters, polyethylene glycol
fatty acid esters, cholesterol, cholesterol esters and sodium salts
of fatty acids.
Esters principally of medium chain-length fatty acids which may be
mentioned are:
monoesters, diesters or polyesters of monohydric or polyhydric,
preferably monohydric to trihydric, saturated C.sub.1 -C.sub.18,
preferably C.sub.2 -C.sub.6, aliphatic alcohols, such as, for
example, methanol, ethanol, ethanediol, propanol, propanediol,
propanetriol, butanol, butane(di-, tri- or tetra-)ol, pentanol,
pentane(di-, tri- or penta-)ol, hexanol, hexane(di-, tri-, tetra-,
penta- or hexa-)ol, octanol, decanol, dodecanol, tetradecanol,
hexadecanol and octadecanol.
Glycerol and propylene 1,2-glycol may be mentioned as
preferred.
The acid component used in the esters are (based on the total
weight as acids) 55 to 100% by weight monobasic or dibasic,
saturated or unsaturated C.sub.6 -C.sub.12, preferably C.sub.8
-C.sub.10, fatty acids (=medium chain-length fatty acids), and 0 to
45% by weight monobasic, dibasic or polybasic, saturated or
unsaturated C.sub.1 -C.sub.5 or C.sub.13 -C.sub.22 carboxylic
acids.
Examples of medium chain-length fatty acids of these types are:
hexanoic acid, hexenoic acid, hexadienoic acid, octanoic acid,
octenoic acid, octa(di- or tri-)enoic acid, decanoic acid, decenoic
acid, deca(di-, tri- or tetra-)enoic acid, dodecanoic acid,
dodeca(di-, tri-, tetra- or penta-)-enoic acid, and all analogous
dioic acids.
Examples of carboxylic acids of this type are:
formic acid, acetic acid, propionic acid, butyric acid, valeric
acid, myristic acid, palmitic acid, stearic acid, arachidic acid,
behenic acid, butenoic acid, hexadecenoic acid, oleic acid,
docosenoic acid, linoleic acid, linolenic acid, arachidonic acid,
malonic acid, succinic acid, glutaric acid, suberic acid,
butenedioic acid, glycolic acid, lactic acid, ricinoleic acid,
malic acid, tartaric acid and citric acid.
Examples of vegetable or animal oils which may be mentioned are soy
bean oil, safflower oil and/or cottonseed oil.
Examples of medicinal active compounds which are sparingly soluble
in water and which may be listed are: corticoids, such as cortisone
acetate, hydrocortisone, dexamethasone and triamcinolone acetonide,
benzodiazepines, such as diazepam and flunitrazepam,
antiepileptics, such as diphenylhydantoin and clonazepam,
chemotherapeutics, such as nitrofurantoin, sulfamethoxazole and
trimethoprim, antimycotics, such as griseofulvin and amphotericin
B, cardiac glycosides, such as digoxin and deslanoside, ergot
alkaloids, such as dihydroergotamine mesilate and ergotamine
tartrate, cytostatics, such as melphalan, barbiturates, such as
pentobarbitone sodium, and lipid-soluble vitamins, such as vitamin
A, B.sub.2, B.sub.6 B.sub.12, E or K.sub.1.
Very particularly important are the dihydropyridine compounds, in
particular those having the following general formula ##STR1## in
which R.sub.1 denotes C.sub.1 -C.sub.4 -alkyl, optionally
substituted by C.sub.1 -C.sub.3 -alkoxy,
R.sub.2 denotes C.sub.1 -C.sub.10 -alkyl, optionally substituted by
C.sub.1 -C.sub.3 -alkoxy, trifluoromethyl or
N-methyl-N-benzylamine,
R.sub.3 denotes C.sub.1 -C.sub.4 -alkyl, cyano or hydroxymethyl,
and
X denotes 2- or 3-nitro, 2,3-dichloro or 2,3- .dbd.N--O--N.dbd.
completing a ring.
Especially preferred are the compounds of the following table:
TABLE
__________________________________________________________________________
##STR2## No. X R.sup.1 R.sup.2 R.sup.3 Generic name
__________________________________________________________________________
1 2-NO.sub.2 CH.sub.3 CH.sub.3 CH.sub.3 Nifedipine 2 3-NO.sub.2
nPrOCH.sub.2 CH.sub.2 nPrOCH.sub.2 CH.sub.2 CH.sub.3 Niludipine 3
3-NO.sub.2 C.sub.2 H.sub.5 CH.sub.3 CH.sub.3 Nitrendipine 4
2-NO.sub.2 CH.sub.3 (CH.sub.3).sub.2 CHCH.sub.2 CH.sub.3
Nisoldipine 5 3-NO.sub.2 CH(CH.sub.3).sub.2
(CH.sub.2).sub.2OCH.sub.3 CH.sub.3 Nimodipine 6 3-NO.sub.2 C.sub.2
H.sub.5 C.sub.10 H.sub.21 (n) CH.sub.3 7 2-Cl CH.sub.3
CH.sub.2CF.sub.3 CH.sub.3 8 2-Cl C.sub.2 H.sub.5 CH.sub.2CF.sub.3
CH.sub.3 9 3-NO.sub.2 CH(CH.sub.3).sub.2 n-PrOCH.sub.2 CH.sub.2
CH.sub.3 10 3-NO.sub.2 CH.sub.3 C.sub.6 H.sub.5 CH.sub.2 N(CH.sub.
3)CH.sub.2 CH.sub.2 CH.sub.3 Nicardipin 11 2,3-Cl.sub.2 C.sub.2
H.sub.5 CH.sub.3 CH.sub.3 Felodipin 12 2,3NON C.sub.2 H.sub.5
C.sub.2 H.sub.5 CH.sub.3 13 2,3NON CH.sub.3 CH(CH.sub.3).sub.2
CH.sub.3 14 3-NO.sub.2 C.sub.2 H.sub.5 C.sub.2 H.sub.5 CH.sub.2 OH
15 3-NO.sub.2 CH.sub.3 CH.sub.3 CN
__________________________________________________________________________
n-Pr = nPropyl
The following may be particularly mentioned: nifedipine,
nimodipine, nitrendipine and nisoldipine.
Likewise important are imidazole derivatives of the formula
##STR3## where R.sub.1 denotes, where appropriate, araylalkyl
chains substituted by chlorine, hydroxyl or arylalkoxy.
Compounds having the following substituents are very particularly
suitable: ##STR4##
In addition, muzolimine and propanidide.
The medicament formulation according to the invention is
advantageously prepared in a two-step process, initially a
pre-emulsification being carried out, and this being followed by a
homogenization process.
The pre-emulsion is prepared by vigorously mixing amounts of the
lipophilic constituents, such as the esters principally of medium
chain-length fatty acids, the vegetable or animal oils, the
medicinal active compound and, where appropriate, benzyl alcohol,
in the appropriate ratios, at temperatures up to 75.degree. C.
until a homogeneous solution or dispersion is produced, and then
vigorously mixing, and, where appropriate, subjecting to a
preliminary reduction in size in a vortex chamber, this mixture
with water which, where appropriate, contains the agent for
producing isotonicity, the emulsifier being introduced either into
the lipophilic phase or the aqueous phase, or in appropriate part
amounts into both phases. The pH of the pre-emulsion is adjusted to
a physiological figure which is optimal for emulsification, for
example 7.6.
This pre-emulsion is then homogenized until an emulsion having a
mean diameter of the lipid droplets of less than 2 .mu.m, in
particular less than 1 .mu.m, is produced.
The homogenization can be carried out by, for example,
high-pressure homogenizers under pressures up to 1,000 bar,
preferably 400 bar or by ultrasonic equipment.
As already mentioned, the advantage of the medicament formulation
according to the invention compared with conventional intravenous
formulations of medicaments which are sparingly soluble in water
comprises, inter alia, the fact that lower amounts of lipid are
required to dissolve the medicament which is sparingly soluble in
water. Due to the lower amounts of lipid, the volume administered
can be reduced to such an extent that medicament therapy of humans
becomes possible. The numerous disadvantages of an excessive
intravenous intake of lipids, such as hyperalimentation, anaemia,
effects on the blood coagulation system, and impairment of liver
function, can be avoided.
As is clear from Table 1 below, the medicinal active compounds
which were investigated as examples show, in the emulsions of some
emulsions of mixed esters of various medium chain-length fatty
acids which were selected as examples, solubilities which ranged
from about twice to more than forty times those in soy bean oil
emulsions.
TABLE 1
__________________________________________________________________________
Comparison of the solubilities of medicaments, which are sparingly
soluble in water, in emulsions of soy oil and various esters
principally of medium chain-length fatty acids (Lipid content of
the emulsions 20% by weight, figures at room temperature) Lipid
phase in Solubility of the medicament in the emulsion % (W/W) the
emulsion Nifedipine Nimodipine Nitrendipine Nisoldipine Muzolimine
Propanidide
__________________________________________________________________________
Ester mixture A 0.08% 0.16% 0.08% 0.14% 0.06% infinitely
principally of miscible medium chain- length fatty acids Ester
mixture B 0.10% 0.26% 0.12% 0.18% 0.06% infinitely principally of
miscible medium chain- length fatty acids Ester mixture C 0.10%
0.50% 0.14% 0.20% 0.32% infinitely principally of miscible medium
chain- length fatty acids Ester mixture D 0.04% 0.08% 0.05% 0.08%
0.02% Soy bean oil 0.02% 0.04% 0.03% 0.04% 0.01% 2.80%
__________________________________________________________________________
Ester mixture A: a glycerol triesters of caprylic acid (70%) and
capric acid (30%)
Ester mixture B: propylene glycol diesters of caprylic acid (75%)
and capric acid (25%)
Ester mixture C: 75% glycerol triesters of caprylic acid (70%) and
capric acid (30%) 12.5% glycerol diesters of caprylic acid (60%)
and capric acid (40%) 12.5% glycerol monoesters of caprylic acid
(60%) and capric acid (40%)
Ester mixture D: 50% soy bean oil and 50% glycerol triesters of
caprylic acid (70%) and capric acid (30%)
The improvement in the solubility of the medicinal active compound
in emulsions of soy bean oil and/or esters of principally medium
chain-length fatty acids which can be achieved by also using benzyl
alcohol is clear from Table 2. As can be seen from the data listed,
a concentration of as little as 5% by weight of benzyl alcohol in
parenteral lipid emulsions leads to an increase in the solubility
of the medicament by a factor of 2.8 to 4.5.
TABLE 2 ______________________________________ Increase in the
solubility of a medicament, which is sparingly soluble in water, in
parenteral lipid emulsions by the addition of benzyl alcohol
(figures at room tempera- ture, lipid content of the emulsion 20%)
Solubility of nimodipine in Solubility of Benzyl alcohol the
emulsion of esters princi- nimodipine in content in the pally of
medium chain- soy bean oil emulsion (% W/W) length fatty acids*
emulsion ______________________________________ 0% 0.16% 0.04% 2%
0.22% 0.08% 4% 0.36% 0.16% 5% 0.46% 0.18%
______________________________________ *triglycerides of medium
chainlength fatty acids comprising 70% caprylic acid and 30% capric
acid were used.
Further advantages of using esters principally of medium
chain-length fatty acids and/or benzyl alcohol comprise the fact
that, after homogenization, smaller droplet diameters, and thus
improved stability of the emulsion, are achieved. Moreover, when
esters principally of saturated medium chain-length fatty acids are
used, there is an improvement in the stability with respect to
lipid oxidation.
The preparation of the medicament formulations may be illustrated
by the examples which follow:
EXAMPLE 1
24.000 g of purified egg-yolk phosphatides are homogeneously
dispersed, at 60.degree. to 70.degree. C., in a mixture of 50.000 g
of purified soy bean oil for injections and 50.000 g of glycerol
triesters of medium chain-length fatty acids, of fatty acid
composition 60% by weight caprylic acid and 40% by weight capric
acid. 0.100 g of nifedipine is added to this mixture, protected
from light. After stirring in 7.500 g of glycerol and 292.500 g of
water for injection, a pre-emulsion is produced and, after
adjusting the pH to 8.2, this is homogenized by passing through a
commercial high-pressure homogenizer at 400 bar 5 times. The
extremely fine emulsion produced is, at 20.degree. C., made to a
volume of 1 liter with an aqueous phase comprising 975.000 g of
water for injections and 25.000 g of glycerol, and is filtered and
dispensed into lightproof 50 ml injection vials under an atmosphere
of nitrogen.
EXAMPLE 2
6.000 g of purified soy bean phosphatides are dissolved in a
mixture of 50.000 g of purified soy bean oil for injections and
50.000 g of benzyl alcohol at 50.degree. C. 0.100 g of nisoldipine
is dissolved in this solution, protected from light. After stirring
in 150.000 g of water for injections, a pre-emulsion is produced
and, after adjusting the pH to 7.6, this is homogenized as
described in Example 1. After making up to 1 liter at 20.degree. C.
with water for injections, the mixture is dispensed into lightproof
2 ml ampules, protected from light and under an atmosphere of
nitrogen.
EXAMPLE 3
15.000 g of purified soy bean phosphatides are dissolved in a
mixture of 200 g of glycerol triesters of caprylic acid (50% by
weight), capric acid (34% by weight) and succinic acid (16% by
weight) and 10.000 g of benzyl alcohol at 50.degree. C. 0.500 g of
nitrendipine is dissolved in this solution, protected from light.
After stirring in 12.000 g of glycerol and 588.000 g of water, a
pre-emulsion is produced, and this is homogenized as described in
Example 1. After making up to 1 liter at 20.degree. C. with an
aqueous phase comprising 980 g of water for injections and 20 g of
glycerol, the mixture is dispensed into lightproof 10 ml ampules,
protected from light and under an atmosphere of nitrogen .
EXAMPLE 4
2.000 g of muzolimine are dissolved in a mixture of 150.000 g of
glycerol triesters of caprylic acid (70% by weight) and capric acid
(30% by weight), 25.000 g of glycerol diesters of caprylic acid
(60% by weight) and capric acid (40% by weight) and 25.000 g of
glycerol monoesters of caprylic acid (60% by weight) and capric
acid (40% by weight). This solution is stirred into 600.00 g of
aqueous phase comprising 16.000 g of Pluronic.RTM.F 68 and 584.000
g of water for injections at 50.degree. C. After homogenization as
described in Example 1, the mixture is made up to 1 liter at
20.degree. C. with water for injections and dispensed into 10 ml
ampules under an atmosphere of nitrogen.
EXAMPLE 5
7.2000 g of purified egg-yolk phosphatides are homogeneously
dispersed, at 60.degree.-70.degree. C., in 60.000 g of glycerol
triesters of caprylic acid (50% by weight), of capric acid (40% by
weight), of linoleic acid (5% by weight) and of caproic and lauric
acids (together 5% by weight). 0.400 g of nimodipine is added to
this mixture, protected from light. After adding 5.550 g of
glycerol and 175.500 g of water for injections and dispersing in a
high-speed vortex chamber, a pre-emulsion is produced and this is
homogenized as described in Example 1. After making up to 1 liter
at 20.degree. C. with an aqueous phase comprising 975.000 g of
water for injections and 25.000 g of glycerol, the mixture is
dispensed into lightproof 50 ml injection vials, protected from
light and under an atmosphere of nitrogen.
EXAMPLE 6
15.000 g of purified soy bean phosphatides are dissolved in a
mixture of 200.000 g of propylene glycol diesters of caprylic acid
(75% by weight) and capric acid (25% by weight) and 15.000 g of
benzyl alcohol at 50.degree. C. 2.000 g of Ketoconazole dissolved
in this solution. After stirring in 14.000 g of glycerol and
586.000 g of water for injections, a pre-emulsion is produced, and
this is homogenized as described in Example 1. After making up to 1
liter at 20.degree. C. with water for injections, the mixture is
dispensed into 10 ml ampules under an atmosphere of nitrogen.
EXAMPLE 7
7.500 g of purified soy bean phosphatides are dissolved in 100.000
g of glycerol triesters of caprylic acid (60% by weight) and capric
acid (40% by weight) at 60.degree.-70.degree. C. 50.000 g of
propanidide are dissolved in this solution. After stirring in
15.000 g of xylitol and 285.000 g of water for injections, a
pre-emulsion is produced, and this is homogenized as described in
Example 1. After making up to 1 liter at 20.degree. C. with an
aqueous phase comprising 950.000 g of water and 50.000 g of
xylitol, the mixture is dispensed into 10 ml ampules under an
atmosphere of nitrogen.
It will be understood that the specification and examples are
illustrative but not limitative of the present invention and that
other embodiments within the spirit and scope of the invention will
suggest themselves to those skilled in the art.
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